Prostate cancer (PC) is the most common cancer and the second leading cause of cancer death in men in the United States. Two major phase III PC chemoprevention trials failed to yield results supportive of Food and Drug Administration (FDA) approval of the respective agents for prevention. Selenium and vitamin E, chosen based on promising secondary endpoints in non-PC prevention trials, both failed to show a benefit in PC reduction in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), although an increase in PC was observed with vitamin E. The Prostate Cancer Prevention Trial (PCPT) demonstrated a decrease in PC risk with finasteride, but cancers that did occur tended to be of higher grade, discouraging approval of the agent for a risk-reducing indication. Thus, a need exists for an effective but non-toxic chemopreventive intervention for PC risk reduction. Aspirin has been shown in multiple observational studies and clinical trials to be associated with reduction in risk of a number of cancers, particularly malignancies of the gastrointestinal tract. This feature, together with its relative non-toxicity and beneficial cardiovascular effects, suggests aspirin as a promising chemopreventive agent. Although the benefits are less for PC than for GI cancers, several meta-analyses have shown a 10% reduction in risk of developing or dying from PC in association with aspirin use. Similarly, randomized trials have demonstrated a decrease in risk of death. Yet, while prevention of colon and mammary cancers with aspirin has been studied extensively in the preclinical setting, no similar studies have been carried out for PC. The mechanisms underlying the preventive activity of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are complex. However, their anti-inflammatory activity, including inhibition of cyclo-oxygenases 1 and 2 (COX-1, 2), resulting in reduction of several prostaglandins (PGs) as well as thromboxane A, have held center stage as potential anti-cancer mechanisms. This may be particularly applicable to PC, which involves inflammation. Additional mechanisms to explain the anti-cancer activity of aspirin and other NSAIDs have been proposed. Among these is enhancement of the immune system, suggesting a potential immunological therapeutic effect by these agents. As one example, evidence suggests that NSAIDs limit carcinogenesis by preventing PGE2-induced maturation of monocytes into immunosuppressive myeloid derived suppressor cells (MDSCs). This additional domain of NSAID activity suggests that combining agents such as aspirin with immunological interventions holds promise in the area of prevention. Prior to combining aspirin/NSAIDs with immune strategies, however, appropriate preclinical studies of the former alone are required. Prior experience has shown that preclinical efficacy studies are critical predictors of outcomes in follow-up clinical trials in humans. A stark example is the negative preventive outcomes observed in the SELECT trial which were predicted by animal studies. A promising example of an animal model of PC is the TMPRSS2-ERG fusion mouse. A recurrent chromosomal rearrangement in PC involves juxtaposition of the 5? untranslated region of the TMPRSS2 gene and ETS family genes, which consist of oncogenic transcription factors such as ERG and ETS. The TMPRSS2 gene is a prostate-specific, androgen-responsive, transmembrane serine protease gene, whereas the ETS and ERG genes encode transcription factors that lead to cell proliferation. Fusions of the TMPRSS2 untranslated 5? exons to the ERG or ETS ?cancer genes? are observed in about 50% of localized prostate cancers and are generally associated with overexpression of the oncogene (?ERG?) component. When fused, upregulation of TMPRSS2 in response to androgen stimulation leads to activation of the ?ERG? gene component and hence to cell proliferation. In the genetically engineered TMPRSS2-ERG fusion mouse model, the TMPRSS2-ERG fusion construct is under the control of the ARR2-Probasin promoter, which has been used in previous models of prostate cancer and prostate intraepithelial neoplasia. However, the TMPRSS2-ERG fusion alone does not induce prostate intraepithelial neoplasia (PIN), a precursor to invasive PC. Rather, it requires concomitant activation of the PI3 kinase pathway, as for example, via inactivation of PTEN. Support for the testing of aspirin in a TMPRSS2-ERG fusion mouse model comes from a small population-based case-control study of PC in which a significant reduction in relative risk with aspirin use was observed for fusion-positive cases, but not fusion-negative cases.